Feedback mechanismsin the interactions between cortical interneurons and pyramidal cells

Abstract

This thesis applies extracellular and single-cell electrophysiological recording techniques, in various in vitro brain slice preparations, to investigate physiological and pathological brain network activity in response to genetic and pharmacological manipulations. Chapter 1 provides a general introduction to the topics relating to this thesis and Chapter 2 gives an overview of the different methodological approaches used in Chapters 3-5. Chapter 3 describes the application of the drug compound 4-tetra Butylbenzaldehyde (4-tBB), a potentiator of intrinsic neuronal homeostatic mechanisms, to organotypic hippocampal slice cultures that exhibit spontaneous seizure-like activity. 4-tBB treatment resulted in altered glutamatergic transmission onto dentate gyrus granule cell and reduced seizure-like activity, highlighting a beneficial role in targeting neuronal homeostasis in the control of network hyperexcitability. Chapter 4 investigates the consequence of PV-specific deletion of the transcriptional coactivator PGC-1α on developing 0 Mg2+-induced epileptiform activity in acute brain slices. Brain slices from PGC-1αPV-/- mice exhibited prolonged preictal stage activity, with more preictal events, delaying onset of seizure-like activity and reducing the number of seizure-like events. This reduced response was attributed to lower levels of local cellular involvement, seen as a reduced gamma/delta power ratio in the LFP, and reduced firing frequency of PVexpressing interneurons (PVINs) and pyramidal cells during preictal network bursts. This work revealed an unexpected anti-epileptic effect of PGC-1α deletion within PVINs. Finally in Chapter 5, an in-depth investigation into the outcome of amyloid β (Aβ) plaque pathology on PVIN and network function was conducted in brain slices from mice harbouring 5 familial Alzheimer’s disease-causing mutations (5xFAD). Using in vitro pharmacological approaches, gamma oscillatory network activity, which is associated with brain circuit function and cognition, was studied in acute brain slices from 5xFAD and control mice. This revealed that gamma oscillations induced by the glutamatergic agonist, kainate, exhibited significant disruptions at early and late disease time points. However, gamma oscillations initiated by cholinergic agonist, carbachol, were relatively stable. Additionally, despite reduced PVIN numbers in 5xFAD tissue at later disease stages, PVIN function during gamma oscillations was remarkably preserved. These various approaches towards studying pathological and physiological network activity provide further insights into cellular feedback mechanisms and brain network function. However, the outcome of these genetic and pharmacological manipulations can be difficult to predict, often resulting in the opposite of what might be expected. Thus, highlighting the difficulty of trying to grasp a complete understanding of cortical network function, given the immense complexity, variability, and adaptability of the system.